One of the more devastating effects of HIV infection is the onset of neurologic dysfunction. A portion of patients with HIV will develop a syndrome of cognitive and motor decline known as HIV associated dementia (HAD). No specific agents for the prevention of treatment of HAD have been identified, perhaps because the pathophysiology of HAD is not completely understood. HIV infected immune cells invade the central nervous system (CNS) early during infection and establish a cascade of events leading to eventual neuronal dysfunction and degeneration. HIV infected monocytes and microglia in the brain release viral proteins, chemokines and cytokines that promote activation of uninfected microglia and astrocytes. The inflammatory response elicited in neuroglia leads to altered metabolism of excitatory amino acids (EAA's) and nitric oxide (NO). The cerebrospinal fluid of HAD patients contains elevated concentrations of EAA's and cytokines known to promote neuronal injury and apoptosis. However, the extent of neuronal apoptosis in HAD patients is not well correlated with cognitive dysfunction. Alternatively, loss of synaptic and dendritic markers is closely associated with behavioral declines. Caspase enzymes, a family of proteases involved in apoptosis, are activated in neurons of HAD patients and in animal models of HAD. Caspase enzyme inhibition also prevents dendrite degeneration in a HAD mouse model. These findings suggest that molecular mediators of apoptosis participate in generating the neuronal dysfunction observed in HAD prior to induction to irreversible apoptosis. Experiments proposed here will examine how the pro-apoptotic transcription factor p53 promotes neuronal injury or dysfunction in tissue culture and in vivo models of HAD. The cellular localization of p53 will be analyzed in HAD cases and several HAD models to determine which cell types respond to HIV with p53 activation. The effect of CNS HIV infection or the HIV coat protein gp120 on initiation of p53-mediated transcription will be assessed. The absence of p53 protects neurons from gp120-induced apoptosis, thus the mechanism of this neuroptrotection will be further defined. Neurotoxic factors released from activated neuroglia that requires p53 for the induction of neuronal injury will be identified. How p53 may promote neurodegeneration through the modulation of caspase enzyme activity will also be studied.